OVERVIEW: What every practitioner needs to know

Are you sure your patient has chikungunya fever? What should you expect to find?

Chikungunya is an acute febrile illness transmitted to humans by mosquitoes. Most infected patients are symptomatic. Infection should be suspected in a returning traveler or contact with a returning traveler from Southeast Asia, Sub-saharan Africa, Italy, or the Caribbean.

Symptoms: The characteristic presentation is an abrupt onset of fever which usually lasts a few days up to 2 weeks. Fever is often accompanied by severe debilitating joint pain. Joint involvement is usually symmetric and most commonly involves wrists, fingers, elbows, ankles, and knees. Rash, headache, fatigue, muscle pain, and nausea may also be seen during the acute phase.

Following the acute presentation, some patients (30-60%) develop prolonged symptoms of incapacitating fatigue, joint pain, and swelling which can last up to 1-2 years and sometimes longer.

How did the patient develop chikungunya fever? What was the primary source from which the infection spread?

Transmission - Chikungunya virus is transmitted by mosquitoes in the Aedes genus (eg. Ae. albopictus, Ae. aegypti). The incubation period is 3-7 days (ranges from 1-12 days). Rarely, blood-borne, in utero, or intrapartum transmission have been reported. Corneal grafts have tested positive for chikungunya, and were shown to transmit infection in animal models.

Epidemiology - Following a large outbreak that originated in Kenya in 2004, local transmission has been reported in most of Subsaharan Africa, Oceania, most of Asia, and Italy and France. In late 2013, local transmission was reported for the first time in the Americas (14 countries/territories in the Caribbean and French Guiana). Prior to 2004, chikungunya was endemic in Africa, SE Asia, and India with periodic outbreaks usually confined to these regions. Given the ubiquitous nature of the mosquito vector and frequent travel between the Caribbean islands, it is anticipated that chikungunya will spread into mainland America.

Which individuals are of greater risk of developing chikungunya fever

It has been estimated that 50-95% of those infected develop symptomatic chikungunya infection. Of these patients, over 50% develop persistent or relapsing joint pain.

Host factors associated with the development of persistent arthralgia/arthritis include age over 45 years, the presence of severe initial joint pain, and underlying osteoarthritis.

Neonates may be more susceptible to encephalopathy and long-term sequelae.

Beware: there are other diseases that can mimic chikungunya fever

The differential diagnosis should take into account travel and exposure history.

Dengue fever

Post-infectious arthritis

Malaria

Leptospirosis

Juvenile rheumatoid arthritis

Other alphavirus infections

Mayaro fever

O’nyong-nyong fever

Ross river fever

Sindbis fever

Barmah Forest

Crimean-Congo fever

Bussuquara fever

Rubella

Parvovirus

Enteroviruses

Measles

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Lymphocytosis or lymphopenia, and thrombocytopenia are frequently seen (though thrombocytopenia and leukopenia are less pronounced than for dengue fever)

Results that confirm the diagnosis

Direct viral detection: Viral isolation, RT-PCR (real-time RT PCR, RT-LAMP). In the acute phase, sera can be used for diagnosis (up to 6 days after onset of illness). Synovial fluid can be tested for the presence of virus in chronic arthritis.

Serologies: IgM (day 4-2 months) and IgG (after day 7) ELISA, neutralization assays, indirect immunofluorescence, hemagglutination inhibition. IgM can last for over 18 months; for serologies measuring IgG, acute and convalescent sera should be obtained, separated by at least 14 days. IgG ELISA may cross-react with other alphaviral infections. Rapid dipstick assays are available, but their performance has not been well characterized.

The Centers for Disease Control and Prevention (CDC) provides diagnostic testing services. Please see complete instructions at www.cdc.gov/ncezid/dvbd/specimensub/arboviral-shipping.html.

What imaging studies will be helpful in making or excluding the diagnosis of chikungunya fever?

Imaging studies are not particularly helpful in the acute phase of illness.

In the prolonged phase, X-rays or MRI may reveal erosive arthritic changes. MRI may also show tenosynovitis. MRI ($$$) is more sensitive than X-rays ($) but neither is necessary for diagnosis.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has disease chikungunya fever, what therapies should you initiate immediately?

Key principles of therapy: Supportive care (fluids, rest, and anti-pyretics) and anti-inflammatory medications (NSAIDS) are the only available therapy. No anti-infective agents have proven to be efficacious.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Treat for malaria in the returning traveler from a malaria endemic area with high fever if not easily distinguishable from chikungunya and pending confirmatory testing.

Patients should be managed as dengue as both are common in similar areas and there is significant overlap of features in both diseases with dengue causing higher mortality. Avoid NSAID use in dengue.

Chikungunya virus and other viruses in the differential have no proven anti-viral therapy that needs to be started empirically.

Other key therapeutic modalities:

Supportive care in the form of rest, fluid resuscitation, and anti-pyretic therapy.

The use of NSAIDS for fever and acute joint pain is helpful.

Physiotherapy is useful to manage prolonged joint problems.

The role of chloroquine, and anti-viral drugs is unclear and unproven.

Corticosteroids should be reserved for severe arthritis not responsive to NSAIDs and used with caution.

What complications could arise as a consequence of chikungunya fever?

What should you tell the family about the patient’s prognosis?

The overall prognosis with chikungunya fever is good. Mortality and complication rate is relatively low except in the elderly with multiple co-morbid conditions.

Individuals >65 years had a 50-fold higher mortality rate when compared to younger adults (<45 years old).

Patients with hypertension, cardiovascular disease, respiratory disease, and alcohol disease appear to have an increased risk of developing atypical disease.

Pregnant women are not at higher risk for complications or long-term sequelae.

Neonates have a higher risk of neurological symptoms and long-term sequelae.

Atypical presentations and severe complications have been noted in immunosuppressed patients.

Prolonged symptoms of a year and up to 3 years are relatively common and need to monitored for - these include fatigue, arthralgias/arthritis, and gait problems. Patients will require outpatient follow up

Severe complications such as liver failure, myocarditis/pericarditis, encephalitis, pneumonia, renal failure, and pancreatitis are uncommon but should be assessed clinically during the acute presentation.

What-if scenarios

If the patient presents with fever and altered mental status, test and treat for Falciparum malaria and/or bacterial meningitis. Cerebrospinal studies (CSF) studies for meningitis and blood smear for malaria should be negative prior to symptomatic management.

Watch out for any of the warning signs of severe dengue (See information in chapter on dengue).

If joints have increased signs of inflammation, septic arthritis may need to be ruled out.

How do you contract chikungunya fever and how frequent is this disease?

Chikungunya virus was first discovered in Tanzania in the 1950s, where it likely originated. It has existed in a sylvatic cycle between forest-dwelling Aedes species mosquitoes and non-human primates in Africa, but is capable of human-to-human transmission utilizing urban Aedes species. The first documented urban outbreak occurred in the early 1960s in Thailand and India, followed by minor outbreaks until 2004.

In 2004, an outbreak on the Kenyan island of Lamu led to >70% of the population becoming infected. This was followed by outbreaks in multiple islands in the Indian Ocean, where large portions of the population (>50%) were affected. Upon introduction to La Reunion island, the virus appears to have undergone a point mutation in the E1 glycoprotein that led to increased infectivity in Aedes albopictus, allowing for transmission in locations with few Aedes aegypti. This strain was then imported to India, leading to a massive epidemic resulting in millions of cases. Subsequent local transmission in Italy and France were reported, as viremic travelers infected local Aedes mosquitoes. In 2013, outbreaks continued to occur in India and Southeast Asia. The new outbreak of chikungunya fever in the Americas is due to a strain most closely related to those recently identified in Indonesia, China, and the Philippines.

Chikungunya fever seasonality most likely coincides with the rainy season, when the vector is most abundant, though this has yet to be well characterized.

Mode of spread: by the inoculation of virus due to an infectious Aedes mosquito bite.

Most epidemiological studies have taken place in La Reunion island or India. These studies have demonstrated that a significant portion of infected patients continue to be symptomatic (most commonly with arthralgia and fatigue) for several years after onset of illness. Mortality directly attributable to chikungunya tends to be low, but overall mortality increases have been observed during epidemics. It remains to be seen whether these results are applicable to the current outbreak in the Caribbean.

Chikungunya virus appears to be maintained in sylvatic cycles in Africa involving non-human primates and Aedes mosquito species. The virus has been isolated from sylvatic mosquitoes. However, data regarding the vertebrate hosts is scarce, with evidence primarily derived from animal serosurveys. In enzootic cycles, it has been postulated that epidemics occur every 3-4 years as vertebrates are repopulated with susceptible young.

What pathogens are responsible for this disease?

Chikungunya virus is a positive-sense single-stranded RNA virus in the genus Alphavirus, family Togaviridae. The alphaviral genus can be divided into New World members that primarily cause encephalitis (e.g. eastern equine encephalitis, Venezuelan equine encephalitis, western equine encephalitis viruses) and Old World members that give rise to arthralgia (e.g. sindbis, Semliki forest, mayaro, chikungunya, Ross river, Barmah forest viruses).

How do these pathogens cause chikungunya fever?

Upon inoculation by an infectious mosquito bite, chikungunya virus infects local fibroblasts. Systemic infection occurs after the virus reaches distant lymph nodes via the bloodstream. The viremic phase is then followed by infection of target organs (primarily mucsle and joints). Chronic arthralgia results from persistent viral infection of joint macrophages, as opposed to a post-infectious inflammatory response. In early infection, type I IFN plays a prominent role in the virus’ ability to replicate. The adaptive immune response is critical to controlling chronic joint disease.

There is evidence that the outbreak strain from La Reunion is associated with increased disease severity and more neurological manifestations than the West African lineage. The chikungunya virus strain circulating in the Caribbean is of Asian lineage, and it remains to be seen how this strain will behave.

What other clinical manifestations may help me to diagnose and manage chikungunya fever?

Short duration of high grade and abrupt onset of fever is the norm. Prolonged fever of >5 days should raise concern for another disease process such as dengue.

There is also a possibility of co-infections with dengue and chikungunya virus, and with malaria and chikungunya virus.

Epidemiological and geographical history is important in generating a differential diagnosis. The various alphaviruses can generally be separated based on these histories.

Skin: Maculopapular rash usually occurs 2-5 days after fever in approximately half of all patients. The rash can also present as a diffuse erythema that blanches with pressure. Photosensitive hyperpigmentation and intertriginous aphthous-like ulcers may be present.

Vesiculobullous dermatosis can be seen in infants and children.

Eyes: Conjunctivitis and episcleritis may be seen.

What other additional laboratory findings may be ordered?

If there are signs and symptoms of meningoencephalitis, a lumbar puncture with cell count, protein, glucose, routine cultures and chikungunya virus RT-PCR could be sent.

In the event of persistent arthritis, synovial fluid could be sent for RT-PCR.

How can the disease chikungunya fever be prevented?

Aedes mosquitoes are indoor and outdoor day biters. In areas with known transmission, mosquito repellent should be applied. During the febrile period of the disease, suspected cases should remain under mosquito nets to prevent transmission to household members. Larval breeding sites should be eliminated. Typically, these include peri-domestic and household containers.

(Provides clinical and laboratory features to distinguish chikungunya from dengue fever. Dengue patients more frequently had lower platelet counts and the presence of bleeding, whereas chikungunya patients had more myalgia or arthralgia.)